CN113493454A - Quinolizine aza double aromatic ring axial chiral compound and its synthesis method - Google Patents
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Abstract
The invention discloses a quinolizine aza double aromatic ring axial chiral compound and a synthesis method thereof. The method comprises the steps of firstly, substituting 1-naphthylyne with methyl chloroformate to obtain an intermediate under the action of lithium diisopropylamide, then, generating a precursor with 2-methylpyridine under the action of lithium diisopropylamide, and finally, reacting the precursor under the action of CuCl and chiral phosphoramide ligand to obtain the quinolizine aza-biaromatic axial chiral compound. The method has mild reaction conditions and extremely high yield and corresponding selectivity, synthesizes the quinolizine aza-biaromatic ring axis chiral compound taking quinolizine as a matrix for the first time, and greatly expands the range of the aza-axis chiral compound.
Description
Technical Field
The invention relates to a quinolizine aza double aromatic ring axial chiral compound and a synthetic method thereof, belonging to the technical field of organic synthetic chemistry.
Background
The chiral compounds with double aromatic ring axes widely exist in natural products, drug molecules and asymmetric catalysis, wherein the chiral compounds with double aromatic ring axes aza changes the electrical distribution of the whole molecule due to the introduction of nitrogen atoms, greatly influences the chemical properties of the molecule, and enables the molecule to have higher physiological activity (Y. -B.Wang, B.Tan, Acc.chem.Res.,2018,51, 534-one 547.). In addition, the existence of the lone pair of electrons on the introduced nitrogen atom also enables the molecules to be widely applied to asymmetric catalysis. For example, the QUINAP ligand constructed based on isoquinoline skeleton, in which nitrogen atom on isoquinoline and introduced phosphine atom act together to form chelating bidentate ligand, which can coordinate with a series of transition metals to form stable complex and play an important role in the construction of corresponding selective C-C bond and C-hetero bond (b.v. rokadem, p.j. guiry, ACS cat.2018, 8,1, 624-one 643).
Also an azanaphthalene ring, unlike quinoline and isoquinoline, the quinolizine nitrogen atom is in the bridgehead position, which makes this class of molecules much different from quinoline and isoquinoline in aromaticity as well as chemical properties. As such, natural products and drug molecules based on the quinolizine backbone are extensively studied by chemists (a.wiles, a.hashimoto, j.a.thanassi, j.cheng, c.d.incarviyo, m.deshpande, m.j.pucci, b.j.bradbury, j.med.chem.,2006,49, 39-42). The current research is mainly focused on the total synthesis of natural products containing quinolizine frameworks, the preparation of related physiologically active materials, the synthesis of DNA intercalators taking quinolizine as parent frameworks and the like. However, the conditions for synthesizing the quinolizine skeleton are often severe, the functional group compatibility is poor, and the like, so that no report is found about synthesizing the axial chiral compound with the quinolizine skeleton.
Disclosure of Invention
The invention discloses a quinolizine aza double aromatic ring axial chiral compound and a synthetic method thereof for the first time.
The quinolizine aza-biaromatic ring axial chiral compound has the following structural formula:
In a particular embodiment of the invention, R is selected from ethoxy, dibenzylamino, methyl or bromo.
A synthetic method of a quinolizine aza-biaromatic axial chiral compound uses CuCl as a catalyst and chiral phosphamide ligand as a chiral source to efficiently convert a synthetic precursor into the quinolizine aza-biaromatic axial chiral compound, and the synthetic route is as follows:
(1) the intermediate 1 is obtained by substituting 1-naphthylyne and methyl chloroformate with raw materials under the action of lithium diisopropylamide, wherein R is selected from alkoxy, substituted amino, alkyl or halogen, and the reaction general formula is as follows:
(2) the intermediate 1 and 2-methyl pyridine are reacted under the action of lithium diisopropylamide to obtain a precursor 2, and the reaction general formula is as follows:
(3) the precursor 2 reacts under the action of CuCl and chiral phosphamide ligand to obtain the quinolizine aza-biaromatic ring axis chiral compound, and the reaction general formula is as follows:
the structural formula of the chiral phosphoramide ligand is as follows:
the invention relates to a synthetic method of a quinolizine aza-biaromatic ring axial chiral compound, which comprises the following steps:
step 1, dropwise adding lithium diisopropylamide into a tetrahydrofuran solution substituted for 1-naphthylalkyne at-78 +/-5 ℃ under the protection of argon, reacting for 1 +/-0.1 h, adding methyl chloroformate into the system, after the reaction is finished, using saturated ammonium chloride to extract and kill, adding water for dilution, then using ethyl acetate for extraction, using saturated sodium chloride solution to wash an organic phase, drying with anhydrous magnesium sulfate, spin-drying a solvent to obtain a crude product, and performing column chromatography purification to obtain an intermediate 1;
and 3, dissolving the precursor 2, CuCl, chiral phosphoramide ligand and binaphthol phosphoric acid in toluene, reacting at room temperature for 36 +/-1 h, washing with a saturated sodium chloride solution after the reaction is finished, drying with anhydrous magnesium sulfate, spin-drying the solvent to obtain a crude product, and finally purifying by column chromatography to obtain the quinolizine aza-biaromatic axis chiral compound.
Preferably, in step 1, the concentration of the substituted 1-naphthoyne in tetrahydrofuran is 0.5M.
Preferably, in the step 1, the molar ratio of the substituted 1-naphthylalkyne to lithium diisopropylamide is 1: 1.2-1.3.
Preferably, in the step 1, the molar ratio of the substituted 1-naphthylalkyne to the methyl chloroformate is 1: 1.3-1.4.
Preferably, in step 2, the concentration of the 2-methylpyridine in tetrahydrofuran is 0.3M.
Preferably, in the step 2, the molar ratio of the 2-methylpyridine to the lithium diisopropylamide is 1: 1.2-1.2.
Preferably, in the step 2, the molar ratio of the 2-methylpyridine to the intermediate 1 is 1: 1.2-1.3.
Preferably, in step 3, the concentration of the precursor 2 in toluene is 0.1M.
Preferably, in step 3, the molar amount of CuCl is 10% of precursor 2.
Preferably, in step 3, the chiral phosphoramide ligand is present in a molar amount of 15% of precursor 2.
Preferably, in the step 3, the molar ratio of the binaphthol phosphoric acid to the precursor 2 is 1: 1-1.1.
Compared with the prior art, the invention has the following advantages:
(1) the invention synthesizes the quinolizine aza-biaromatic ring axis chiral compound which takes quinolizine as a matrix for the first time, and greatly expands the range of aza-axis chiral compounds;
(2) the method has the advantages of mild reaction conditions, extremely high yield and corresponding selectivity, good atom economy, good compatibility of reaction functional groups, convenience for subsequent expansion and conversion into higher-value derivatives;
(3) the quinolizine aza double aromatic ring axis chiral compound can form a quinolizine aza double aromatic ring axis chiral thiourea bifunctional catalyst through a series of conversions, the catalyst can be applied to asymmetric Michael addition reaction, and better products and enantioselectivity are obtained; in addition, the quinolizine aza-biaromatic ring axis chiral compound can be used as a mother nucleus to synthesize a series of DNA intercalators, physiological materials of quinolizine frameworks and the like, and the DNA intercalators of the current racemic quinolizine frameworks and the like are expanded into the chiral DNA intercalators, so that the physiological activity of the quinolizine aza-biaromatic ring axis chiral compound is researched.
Drawings
FIG. 1 is the nuclear magnetic hydrogen spectrum of the quinolizine aza-biaromatic ring axis chiral compound prepared in example 1.
FIG. 2 is the nuclear magnetic carbon spectrum of the quinolizine aza-biaromatic ring axial chiral compound prepared in example 1.
FIG. 3 is the nuclear magnetic hydrogen spectrum of the quinolizine aza-biaromatic ring axis chiral compound prepared in example 2.
FIG. 4 is the nuclear magnetic carbon spectrum of the quinolizine aza-biaromatic ring axial chiral compound prepared in example 2.
FIG. 5 is the nuclear magnetic hydrogen spectrum of the quinolizine aza-biaromatic ring axis chiral compound prepared in example 3.
FIG. 6 is the nuclear magnetic carbon spectrum of the quinolizine aza-biaromatic ring axial chiral compound prepared in example 3.
FIG. 7 is the nuclear magnetic hydrogen spectrum of the quinolizine aza-biaromatic ring axis chiral compound prepared in example 4.
FIG. 8 is the nuclear magnetic carbon spectrum of the quinolizine aza-biaromatic ring axial chiral compound prepared in example 4.
FIG. 9 shows the nuclear magnetic hydrogen spectrum of the quinolizine aza-biaromatic axis chiral compound prepared in example 5.
FIG. 10 is the nuclear magnetic carbon spectrum of the quinolizine aza-biaromatic ring axial chiral compound prepared in example 5.
FIG. 11 is the nuclear magnetic hydrogen spectrum of the quinolizine aza-biaromatic axis chiral compound prepared in example 6.
FIG. 12 is the nuclear magnetic carbon spectrum of the quinolizine aza-biaromatic ring axial chiral compound prepared in example 6.
Detailed Description
The invention is described in more detail below with reference to examples and figures. The chiral phosphoramide ligands employed in the examples below were purchased directly.
Example 1
R is OEt, and the molecular structure of the quinolizine aza double aromatic ring axial chiral compound is as follows:
dissolving 1-ethynyl-2-ethoxynaphthalene in tetrahydrofuran solution under the protection of argon, reducing the temperature of a reaction system to-78 +/-5 ℃, and then adding lithium diisopropylamide solution; after the system reacts for 1 +/-0.1 h at the same temperature, methyl chloroformate is added, the reaction is continued at the same temperature, and after ten minutes, saturated ammonium chloride solution is added for quenching. The reaction solution was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography after spin-drying the solvent to obtain intermediate 1. Cooling a tetrahydrofuran solution of 2-methylpyridine to-78 +/-5 ℃, then adding a lithium diisopropylamide solution, reacting the system at the same temperature for 1 +/-0.1 h, adding the obtained intermediate 1, continuing to react at the same temperature for 1 +/-0.1 h, after the reaction is finished, carrying out extraction quenching reaction by using a saturated ammonium chloride solution, extracting by using ethyl acetate, washing an organic phase by using saturated saline solution, drying the organic phase by using anhydrous magnesium sulfate, spin-drying the solvent, and purifying by using column chromatography to obtain a precursor 2. Adding the precursor 2, CuCl, chiral phosphoramide ligand, binaphthol phosphate and toluene into a reaction bottle, and placing the reaction bottle at room temperature for reaction for 36 +/-1 h. After the reaction is finished, saturated ammonium chloride solution is used for extraction and sterilization, ethyl acetate is used for extraction, saturated saline solution is used for washing an organic phase, the organic phase is dried by anhydrous magnesium sulfate, the solvent is dried in a spinning mode, column chromatography purification is used for obtaining the target molecule, the yield is 88%, and the ee value is 92%.
HPLCdata(Chiralpak OD column,hexane:isopropanol＝70:30,1.0mL/min):tr＝8.1min(major),tr＝15.6min(minor),ee＝92％.
Example 2
R is NBn2The molecular structure of the quinolizine aza-biaromatic ring axial chiral compound is as follows:
dissolving 1-ethynyl-2-dibenzyl aminonaphthalene in tetrahydrofuran solution under the protection of argon, reducing the temperature of a reaction system to-78 +/-5 ℃, and then adding lithium diisopropylamide solution; after the system reacts for 1 +/-0.1 h at the same temperature, methyl chloroformate is added, the reaction is continued at the same temperature, and after ten minutes, saturated ammonium chloride solution is added for quenching. The reaction solution was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography after spin-drying the solvent. Intermediate 1 is obtained. Cooling a tetrahydrofuran solution of 2-methylpyridine to-78 +/-5 ℃, then adding a lithium diisopropylamide solution, reacting the system at the same temperature for 1 +/-0.1 h, adding the obtained intermediate 1, continuing to react at the same temperature for 1 +/-0.1 h, after the reaction is finished, carrying out extraction quenching reaction by using a saturated ammonium chloride solution, extracting by using ethyl acetate, washing an organic phase by using saturated saline solution, drying the organic phase by using anhydrous magnesium sulfate, spin-drying the solvent, and purifying by using column chromatography to obtain a precursor 2. Adding the precursor 2, CuCl, chiral phosphoramide ligand, binaphthol phosphate and toluene into a reaction bottle, and placing the reaction bottle at room temperature for reaction for 36 +/-1 h. After the reaction is finished, saturated ammonium chloride solution is used for extraction and sterilization, ethyl acetate is used for extraction, saturated saline solution is used for washing an organic phase, the organic phase is dried by anhydrous magnesium sulfate, the solvent is dried in a spinning mode, column chromatography purification is used for obtaining the target molecule, the yield is 83%, and the ee value is 97%.
HPLC data(Chiralpak AD column,hexane:isopropanol＝70:30,1.0mL/min):tr＝10.5min(major),tr＝17.1min(minor),ee＝97％.
Example 3
R is Me, and the molecular structure of the quinolizine aza double aromatic ring axial chiral compound is as follows:
dissolving 1-ethynyl-2-methylnaphthalene in tetrahydrofuran solution under the protection of argon, reducing the temperature of a reaction system to-78 +/-5 ℃, and then adding lithium diisopropylamide solution; after the system reacts for 1 +/-0.1 h at the same temperature, methyl chloroformate is added, the reaction is continued at the same temperature, and after ten minutes, saturated ammonium chloride solution is added for quenching. The reaction solution was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography after spin-drying the solvent. Intermediate 1 is obtained. Cooling a tetrahydrofuran solution of 2-methylpyridine to-78 +/-5 ℃, then adding a lithium diisopropylamide solution, reacting the system at the same temperature for 1 +/-0.1 h, adding the obtained intermediate 1, continuing to react at the same temperature for 1 +/-0.1 h, after the reaction is finished, carrying out extraction quenching reaction by using a saturated ammonium chloride solution, extracting by using ethyl acetate, washing an organic phase by using saturated saline solution, drying the organic phase by using anhydrous magnesium sulfate, spin-drying the solvent, and purifying by using column chromatography to obtain a precursor 2. Adding the precursor 2, CuCl, chiral phosphoramide ligand, binaphthol phosphate and toluene into a reaction bottle, and placing the reaction bottle at room temperature for reaction for 36 +/-1 h. After the reaction is finished, saturated ammonium chloride solution is used for extraction and sterilization, ethyl acetate is used for extraction, saturated saline solution is used for washing an organic phase, the organic phase is dried by anhydrous magnesium sulfate, the solvent is dried in a spinning mode, column chromatography purification is used for obtaining the target molecule, the yield is 83%, and the ee value is 97%.
HPLC data(Chiralpak OD column,hexane:isopropanol＝70:30,1.0mL/min):tr＝36.4min(major),tr＝46.4min(minor),ee＝86％.
Example 4
R is Br, the molecular structure of the quinolizine aza-biaromatic ring axial chiral compound is as follows:
dissolving 1-ethynyl-2-bromonaphthalene in tetrahydrofuran solution under the protection of argon, reducing the temperature of a reaction system to-78 +/-5 ℃, and then adding lithium diisopropylamide solution; after the system reacts for 1 +/-0.1 h at the same temperature, methyl chloroformate is added, the reaction is continued at the same temperature, and after ten minutes, saturated ammonium chloride solution is added for quenching. The reaction solution was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography after spin-drying the solvent. Intermediate 1 is obtained. Cooling a tetrahydrofuran solution of 2-methylpyridine to-78 +/-5 ℃, then adding a lithium diisopropylamide solution, reacting the system at the same temperature for 1 +/-0.1 h, adding the obtained intermediate 1, continuing to react at the same temperature for 1 +/-0.1 h, after the reaction is finished, carrying out extraction quenching reaction by using a saturated ammonium chloride solution, extracting by using ethyl acetate, washing an organic phase by using saturated saline solution, drying the organic phase by using anhydrous magnesium sulfate, spin-drying the solvent, and purifying by using column chromatography to obtain a precursor 2. Adding the precursor 2, CuCl, chiral phosphoramide ligand, binaphthol phosphate and toluene into a reaction bottle, and placing the reaction bottle at room temperature for reaction for 36 +/-1 h. After the reaction is finished, saturated ammonium chloride solution is used for extraction and sterilization, ethyl acetate is used for extraction, saturated saline solution is used for washing an organic phase, the organic phase is dried by anhydrous magnesium sulfate, the solvent is dried in a spinning mode, column chromatography purification is used for obtaining the target molecule, the yield is 83%, and the ee value is 97%.
HPLC data(Chiralpak AD column,hexane:isopropanol＝70:30,1.0mL/min):tr＝17.1min(minor),tr＝22.0min(major),ee＝66％.
Example 5
R is free amino, and the molecular structure of the quinolizine aza-biaromatic ring axial chiral compound is as follows:
the target molecule obtained in example 2 was dissolved in methanol solution (0.5M), PdOH/C (10 mol%) was added, followed by a solution in H2And reacting at room temperature for 20 +/-1 h under an atmosphere. After the reaction is finished, filtering by using kieselguhr, spin-drying the filtrate, and purifying by column chromatography to obtain the target molecule, wherein the yield is 90%, and the ee value is 96%.
HPLC data(Chiralpak AD column,hexane:isopropanol＝70:30,1.0mL/min):tr＝11.3min(major),tr＝13.4min(minor),ee＝99％.
Example 6
R is thiourea derivative, and the structure of the novel thiourea catalyst based on the quinolizine skeleton is as follows:
the aromatic amine obtained in example 5 above was dissolved in methylene chloride (0.5M), and aryl isothiocyanate (1.2eq) was added to react at room temperature for 24. + -.1 h. And after the reaction is finished, adding a saturated ammonium chloride solution for extraction, extracting by using dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, spin-drying the organic phases, and purifying by using column chromatography to obtain the target molecule. The yield was 67% and ee was 96%.
HPLC data(Chiralpak OD column,hexane:isopropanol＝70:30,1.0mL/min):tr＝4.3min(major),tr＝6.7min(minor),ee＝96％.
Example 7
Cyclohexenone (1.0eq) was dissolved in dichloromethane (0.1M), the thiourea catalyst from example 6 (10 mol%) was added, the reaction was cooled to-60 ± 2 ℃, then p-toluene thiophenol (1.2eq) was added, the reaction was allowed to react at this temperature for 48 ± 2h, sodium bicarbonate solution was added and quenched, extracted with dichloromethane, the organic phases were combined and dried over anhydrous magnesium sulfate, the organic phase was spin-dried and purified using column chromatography to give the target molecule. The yield was 76% and ee was 39%.
HPLC data(Daicel Chiralpak AD column,hexane:isopropanol＝90:10,1.0mL/min):tr＝6.3min(major),tr＝7.1min(minor),ee＝39％.
Comparative example 1
This comparative example is essentially the same as the examples, except that no binaphthol phosphate was added as an additive.
Dissolving 1-ethynyl-2-ethoxynaphthalene in tetrahydrofuran solution under the protection of argon, reducing the temperature of a reaction system to-78 +/-5 ℃, and then adding lithium diisopropylamide solution; after the system reacts for 1 +/-0.1 h at the same temperature, methyl chloroformate is added, the reaction is continued at the same temperature, and after ten minutes, saturated ammonium chloride solution is added for quenching. The reaction solution was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography after spin-drying the solvent. Intermediate 1 is obtained. Cooling a tetrahydrofuran solution of 2-methylpyridine to-78 +/-5 ℃, then adding a lithium diisopropylamide solution, reacting the system at the same temperature for 1 +/-0.1 h, adding the obtained intermediate 1, continuing to react at the same temperature for 1 +/-0.1 h, after the reaction is finished, carrying out extraction quenching reaction by using a saturated ammonium chloride solution, extracting by using ethyl acetate, washing an organic phase by using saturated saline solution, drying the organic phase by using anhydrous magnesium sulfate, spin-drying the solvent, and purifying by using column chromatography to obtain a precursor 2. Adding the precursor 2, CuCl, chiral phosphoramide ligand and toluene into a reaction bottle, and placing the reaction bottle at room temperature for reaction for 36 +/-1 h. After the reaction is finished, saturated ammonium chloride solution is used for extraction and sterilization, ethyl acetate is used for extraction, saturated saline solution is used for washing an organic phase, the organic phase is dried by anhydrous magnesium sulfate, the solvent is dried in a spinning mode, column chromatography purification is used for obtaining the target molecule, the yield is 51%, and the ee value is 90%.
Comparative example 2
This comparative example is essentially the same as example 1, except that the reaction solvent is dichloromethane.
Dissolving 1-ethynyl-2-ethoxynaphthalene in tetrahydrofuran solution under the protection of argon, reducing the temperature of a reaction system to-78 +/-5 ℃, and then adding lithium diisopropylamide solution; after the system reacts for 1 +/-0.1 h at the same temperature, methyl chloroformate is added, the reaction is continued at the same temperature, and after ten minutes, saturated ammonium chloride solution is added for quenching. The reaction solution was extracted with ethyl acetate, and the obtained organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and purified by column chromatography after spin-drying the solvent. Intermediate 1 is obtained. Cooling a tetrahydrofuran solution of 2-methylpyridine to-78 +/-5 ℃, then adding a lithium diisopropylamide solution, reacting the system at the same temperature for 1 +/-0.1 h, adding the obtained intermediate 1, continuing to react at the same temperature for 1 +/-0.1 h, after the reaction is finished, carrying out extraction quenching reaction by using a saturated ammonium chloride solution, extracting by using ethyl acetate, washing an organic phase by using saturated saline solution, drying the organic phase by using anhydrous magnesium sulfate, spin-drying the solvent, and purifying by using column chromatography to obtain a precursor 2. Adding the precursor 2, CuCl, chiral phosphoramide ligand, binaphthol phosphate and dichloromethane into a reaction bottle, and placing the reaction bottle at room temperature for reaction for 36 +/-1 h. After the reaction is finished, saturated ammonium chloride solution is used for extraction and sterilization, ethyl acetate is used for extraction, saturated saline solution is used for washing an organic phase, the organic phase is dried by anhydrous magnesium sulfate, the solvent is dried in a spinning mode, column chromatography purification is used for obtaining the target molecule, the yield is 80%, and the ee value is 85%.
Claims (10)
1. The quinolizine aza double aromatic ring axial chiral compound is characterized in that the structural formula is as follows:
2. The quinolizine aza bis-aromatic-axis chiral compound of claim 1 wherein R is selected from ethoxy, dibenzylamino, methyl or bromo.
3. The synthetic method of the quinolizine aza-biaromatic axis chiral compound as claimed in claim 1 or 2, characterized in that the synthetic route is as follows:
(1) the intermediate 1 is obtained by substituting 1-naphthylyne and methyl chloroformate with raw materials under the action of lithium diisopropylamide, wherein R is selected from alkoxy, substituted amino, alkyl or halogen, and the reaction general formula is as follows:
(2) the intermediate 1 and 2-methyl pyridine are reacted under the action of lithium diisopropylamide to obtain a precursor 2, and the reaction general formula is as follows:
(3) the precursor 2 reacts under the action of CuCl and chiral phosphamide ligand to obtain the quinolizine aza-biaromatic ring axis chiral compound, and the reaction general formula is as follows:
the structural formula of the chiral phosphoramide ligand is as follows:
the method comprises the following specific steps:
step 1, dropwise adding lithium diisopropylamide into a tetrahydrofuran solution substituted for 1-naphthylalkyne at-78 +/-5 ℃ under the protection of argon, reacting for 1 +/-0.1 h, adding methyl chloroformate into the system, after the reaction is finished, using saturated ammonium chloride to extract and kill, adding water for dilution, then using ethyl acetate for extraction, using saturated sodium chloride solution to wash an organic phase, drying with anhydrous magnesium sulfate, spin-drying a solvent to obtain a crude product, and performing column chromatography purification to obtain an intermediate 1;
step 2, dropwise adding lithium diisopropylamide into a tetrahydrofuran solution of 2-methylpyridine at-78 +/-5 ℃ under the argon protection atmosphere, reacting for 1 +/-0.1 h, adding the intermediate 1 into the reaction solution, reacting for 1 +/-0.1 h, after the reaction is finished, quenching with saturated ammonium chloride, adding water for dilution, extracting with ethyl acetate, washing an organic phase with a saturated sodium chloride solution, drying with anhydrous magnesium sulfate, spin-drying the solvent to obtain a crude product, and purifying by column chromatography to obtain a precursor 2;
and 3, dissolving the precursor 2, CuCl, chiral phosphoramide ligand and binaphthol phosphoric acid in toluene, reacting at room temperature for 36 +/-1 h, washing with a saturated sodium chloride solution after the reaction is finished, drying with anhydrous magnesium sulfate, spin-drying the solvent to obtain a crude product, and finally purifying by column chromatography to obtain the quinolizine aza-biaromatic axis chiral compound.
4. The method of claim 3, wherein in step 1, the concentration of the substituted 1-naphthoyne in tetrahydrofuran is 0.5M.
5. The synthesis method according to claim 3, wherein in the step 1, the molar ratio of the substituted 1-naphthylyne to lithium diisopropylamide is 1: 1.2-1.3, and the molar ratio of the substituted 1-naphthylyne to methyl chloroformate is 1: 1.3-1.4.
6. The method of claim 3, wherein in step 2, the concentration of 2-methylpyridine in tetrahydrofuran is 0.3M.
7. The synthesis method according to claim 3, wherein in the step 2, the molar ratio of the 2-methylpyridine to the lithium diisopropylamide is 1: 1.2-1.2, and the molar ratio of the 2-methylpyridine to the intermediate 1 is 1: 1.2-1.3.
8. The synthesis method according to claim 3, wherein in step 3, the concentration of the precursor 2 in toluene is 0.1M.
9. The method as claimed in claim 3, wherein in step 3, the molar amount of CuCl is 10% of that of the precursor 2, and the molar amount of chiral phosphoramide ligand is 15% of that of the precursor 2.
10. The synthesis method according to claim 3, wherein in the step 3, the molar ratio of the binaphthol phosphate to the precursor 2 is 1: 1-1.1.
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